Obesity is highly prevalent in America (greater than 30% of adults) and predisposes patients to a host of disorders from diabetes to cardiovascular disease. Low-carbohydrate, high-fat diets (e.g., the Atkins diet) is a popular and effective choice to lose weight. The major goal of these diets is to induce ketosis, a process by which the liver converts fatty acids to ketone bodies providing an alternative fuel in the face of limited glucose availability. Enthusiasm for these ketogenic diets (KD) is tempered by recent evidence suggesting an increased risk of mortality from cardiovascular events for individuals consuming these diets. KD may increase cardiovascular risk and other adverse outcomes as it induces excessive, chronic activation of stress regulatory systems, including the hypothalamic pituitary adrenal axis (HPA) and sympathetic branch of the autonomic nervous system, despite decreased body weight gain. KD induces cardiac hypertrophy and kidney pathology as well as increasing neuronal activation in stress regulatory brain regions including the periventricular nucleus of the hypothalamus (PVN). Hormonal fibroblast growth factor 21 (FGF21) is necessary and sufficient for the effects of KD on HPA and cardiovascular endpoints. The liver produces FGF21 during ketosis that can cross the blood-brain barrier and act on its receptor (FGFR1) present in the brain. KD activates PVN microglia that express FGFR1, suggesting that KD-induced FGF21 may increase neuronal activation by inducing neuroinflammation. FGFR1 is also expressed on PVN neurons where it activates pCREB, a signaling pathway that is critical for synaptic remodeling, suggesting that FGF21 may modulate HPA activity by inducing plasticity. Thus, this project will test the hypothesis that FGF21 increases sympathetic and HPA tone by inducing neuroinflammation and/or synaptic remodeling in stress regulatory brain regions. Pharmacological anti-inflammatory intervention and CREB anti-sense ODN will be used to test whether neuroinflammation and pCREB-dependent synaptic remodeling respectively, are necessary for FGF21-mediated effects. The research project has important implications for individuals using KD and suggests they may be at greater risk for stress and cardiovascular diseases, particularly via the actions of FGF21. This project will elucidate the mechanisms by which sympathetic and HPA activity are modulated, specifically identifying the contributions of neuroinflammation and synaptic remodeling. Significantly, after studying inflammation in her dissertation work, Dr. Packard plans to use this postdoctoral training with Dr. Ulrich-Lai (sponsor; expert in stress regulation, stress/diet interactions and synaptic plasticity) and Dr. Woods (co-sponsor; expert in diet, metabolism and obesity) to enable her long term career goal of being an independent, academic researcher at the junction of fields of neuroimmunology, neuroendocrinology and metabolism.